The present invention relates to methods and compositions for treating ovarian cancer in humans. More particularly, the present invention relates to methods for treating ovarian cancer using a taxane composition.
Ovarian cancer is the fourth most frequent cause of cancer death in females and in the United States, accounts for approximately 13,000 deaths annually. Moreover, the incidence is rising in industrialized countries. The etiology of the neoplastic transformation remains unknown although there is epidemiological evidence for an association with disordered endocrine function. The incidence of ovarian carcinoma is higher in nulliparous females and in those with early menopause.
Chemotherapy remains the major treatment for patients with advanced ovarian cancer. Alkylating agents induce a response in 33-65% of patients. Such alkylating agents include, but are not limited to chlorambucil, thio-tepa, and cyclophosphamide. Other agents are also known to be effective. Of these, cisplatin and carboplatin are considered to be the single most active cytotoxic agents and the response rate appears to be related to dose. A recent meta-analysis involving most of the major chemotherapy clinical trials of the 1980s in patients with ovarian cancer concluded that platinum-based therapies were the single most effective agents. It was also found that these platinum-based therapies were more effective when given in combination with another agent than when given alone. Cisplatin was also the first cytotoxic agent to demonstrate usefulness as second-line therapy, i.e., treatment for patient whose tumor had relapsed following first-line treatment with alkylating agent therapy.
In the late 1980s, several clinical studies were performed which led to the availability and use of paclitaxel in patients with ovarian cancer. Paclitaxel is now approved for use as a second-line treatment in many countries and is being evaluated as a component of front-line therapy in combination with cisplatin.
Paclitaxel is a novel microtubule stabilizing antitumor agent, originally isolated from the stem bark of Taxus brevifolia, the western (Pacific) yew tree. Paclitaxel acts by promoting the formation of unusually stable microtubules, and inhibits the normal dynamic reorganization of the microtubule network required for mitosis and cell proliferation. (See Schiff, P. B., et al (1979) Nature 277,665; Schiff, P. B., et al (1981) Biochemistry 20, 3247). In the presence of paclitaxel, the concentration of tubulin required for polymerization is significantly lowered. Microtubule assembly occurs without GTP and at low temperatures, and the microtubules formed are more stable to depolymerization by dilution, calcium, cold, and inhibitory drugs. Paclitaxel reversibly binds to polymerized tubulin, and other tubulin-binding drugs will bind to tubulin in the presence of paclitaxel.
Paclitaxel interacts with the microtubule system of many types of organisms. For example, in mammalian cells a 50 nM paclitaxel concentration usually causes a significant increase in microtubule number, with changes in cell shape and mitotic arrest in actively dividing cells. (Parness, J., et al. (1982) Biochem. Biophys. Res. Commun. 105, 1082). These perturbations of microtubule function caused by paclitaxel have a critical impact on the cell because of the role played by microtubules in cell motility, secretion, and cell division.
Paclitaxel has been studied for its effect in combating tumor growth in several clinical trials using a variety of administration schedules. Severe allergic reactions have been observed following administration of paclitaxel. However, it has been demonstrated that the incidence and severity of allergic reactions is affected by the rate of paclitaxel infusion (Weiss, R B., et al (1990) J. Clin. Oncol. 8, 1263).
In a study of Taxol(copyright), (trademarked paclitaxel product of Bristol Meyers Squibb), in over 400 patients with ovarian cancer, patients were randomized two ways, (1) between 135 to 175 mg/m2 and (2) between 3-hour and 24-hour infusions. In this study, minor degrees of flushing were seen in 42% but severe hypersensitivity reactions were seen in only 1-2% without influence of dose or schedule on frequency or severity. Neurosensory symptoms, described as burning paresthesia, occurred more frequently (52%) at the 175 mg/m2 dose as compared with 36% at the lower dose. A syndrome of arthralgia, with onset 1-2 days after administration and lasting a few days, was common (55-65%) and more frequent at the higher dose.
Myelosuppression (primarily granulocytopenia) occurred frequently but was most common with the 24-hour infusion (71%). Only 18% of patients receiving drug by a 3-hour infusion developed Grade 4 granulocytopenia. Febrile neutropenia was documented only with the 24-hour infusion. Stomatitis occurred in 22-30% of the patients and was severe in less than 2% of the patients. Cardiovascular effects were rare. Asymptomatic bradycardia (pulse less than 50 beats/min.) was observed in only 1% of cycles (26 of 2354 cycles) and hypotension (systolic  less than 80 mm Hg) in only 13 of 2354 cycles. Nine patients discontinued Taxol(copyright) treatment because of nonhematologic toxicity. Of these patients, 4 had neurotoxicity, 3 had hypersensitivity, 1 had mucositis and 1 had idiopathic pulmonary edema.
Infusion times, from 3 hours up to 24 hours, have been used in treatment with paclitaxel to decrease the incidence of toxicity and side effects, including allergic reactions to the drug. Data from these studies indicate that reversible myelosuppression is the dose limiting toxicity, with significant peripheral neuropathy observed at doses of 275 mg/m2 and greater. Other toxicities include myalgia, mucositis, and alopecia.
Paclitaxel was approved by the FDA in December 1992, for treatment of ovarian cancer after failure of first-line or subsequent chemotherapy. This approval was based on the initial Phase II studies and on the National Cancer Institute compassionate plea program, where paclitaxel was administered over a 24-hour period. More recently, the more convenient 3-hour schedule has been approved for the same indication in many countries.
Studies of paclitaxel in breast cancer treatment has been reported. In single agent studies, response rates have been found to be dose related, with a 13-37% response rate for doses of 135 to 175 mg/m2, compared to a 36-71% response rate for doses of 250 mg/m2 with G-CSF. The highest response rate (79%) has been reported in a 600 patient study using paclitaxel (135 mg/m2) in combination with cisplatin (75 mg/m2).
In a European-Canadian multi-institutional trial with ovarian cancer patients, 407 patients were randomized to one of two dose levels (135 mg/m2 or 175 mg/m2), given every three weeks, and to either a 3-hour or 24-hour schedule. See Eisenhauer, E.A. et al xe2x80x9cEuropean-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High dose versus low-dose and long-term versus short infusion.xe2x80x9d J. Clin. Onc. 1994. 12:2654-66. The response rate was higher at the 175 mglm2 dose (20%) than the 135 mg/m2 dose (15%) but the difference was not statistically significant. Time to tumor progression was significantly longer (19 weeks vs 14 weeks) in patients receiving the higher dose. Overall survival based on deaths in about 25% of patients were similar in the different subsets. Thus, the study concluded that the shorter (3-hour) infusion was nearly as efficacious, yet safer and more convenient than the 24-hour infusion.
Paclitaxel, like other chemotherapy agents, has been shown to create drug resistance in tumor cells. Drug resistance by tumor cells is a common response to chemotherapy agents. Two mechanisms of paclitaxel resistance have been identified in vitro. In one cell type, resistance is due to drug efflux, which is the result of increased levels of membrane P-glycoproteins causing increased drug efflux. (Gupta, R. S. (1985) Cancer Treat. Rep. 69, 515). These cells are also resistant to the vinca alkaloids, doxorubicin, and other natural products, and resistance is reversible with calcium channel blockers such as verapamil (Racker, E., et al (1986) Cancer Treat. Rep. 70, 275). Another mechanism of resistance found in other paclitaxel resistant cells involves mutations in the alpha- or beta-tubulin subunits. (Schibler, M. J., et al (1986) J. Cell Biol. 102, 1522).
Experimental evidence suggests that the cytotoxicity of paclitaxel is both schedule-dependent and highly dependent on exposure time. Thus both anti-tumor effect and myelosuppression might be expected to be greater with longer infusions. Longer drug exposure times with some natural agents, including paclitaxel, may also partially overcome multidrug resistance (mdr) associated with the mdr-1 gene. Drug resistance MCF 7 cells were 4.4 fold less resistant to a 24-hour continuous exposure to paclitaxel than to a 3-hour exposure. See Lai, G.M. et al xe2x80x9cP-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines.xe2x80x9d Int. J. Cancer (1991) 49:696-703. Based on this in vitro data, a Phase I/II trial of a 96-hour schedule was completed in doxorubicin or mitoxantrone-refractory breast cancer patients. See Wilson, W. H. et al. xe2x80x9cPaclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion.xe2x80x9d J. Clin. Oncol. (1994) 12:1621-1629. In the Phase II part of the study, breast cancer patient received a dose of 140 mg/m2 taxol (BMS, Bristol Meyers Squibb) over a 96-hour period. A partial response was observed in 16 of 33 patients (48%) and a minor response was observed in 5 (15%). Another report of breast cancer treatment indicated that a 96 hour infusion schedule of taxol (BMS) may be efficacious for breast cancer treatment. See Hochhauser, D. et al, xe2x80x9cEfficacy of prolonged paclitaxel infusion after failure of prior short taxane infusion: A phase II and phamacologic study in metastatic breast cancer. Br. Ca. Res. and Trt. (1994) 32:34. These investigators administered taxol (BMS) via a 96-hour infusion at a total dose of 140 mg/m2 to 25 patients with measurable metastatic breast cancer, in each of whom tumor had progressed during a prior course of either taxol (BMS) by 3 hour infusion or taxotere by 1-hour infusion. 28% of the patients achieved an objective tumor response despite prior clinical evidence of taxane resistance.
What is needed are methods and compositions for treating patients with ovarian cancer. Particularly what is needed are methods and compositions for patients with ovarian cancer who have had tumor progression after treatment with short term infusion schedules of taxanes. Furthermore, no one has been able to demonstrate an effective regimen for treatment of ovarian cancer that overcomes the problem of multi-drug resistance.
Thus, methods and compositions are needed that are capable of treating ovarian cancer that is refractory to short term infusion schedules of taxanes, such as taxotere or paclitaxel. Moreover, an infusion treatment regimen that would be efficacious in treatment of multi-drug resistance ovarian cancer would be beneficial. Additionally, methods and compositions that are easily administered are necessary. In addition to infusion methods, a simple and efficacious method of treatment would be through the oral route.
What is also needed are methods and compositions for treating patients with ovarian cancer who have had tumor progression after treatment with known chemotherapy agents such as platinum-based chemotherapy treatments. What is particularly needed are compositions and methods for treatment of patients with ovarian cancer who have tumor progression after systemic treatment with known chemotherapy agents such as platinum-based chemotherapy treatments and who are refractory to short term infusion (1 to 24 hour) of taxane therapy.
Thus, methods and compositions are needed that are capable of treating ovarian cancer that is refractory to known chemotherapy agents and short term infusion schedules of paclitaxel. Moreover, an infusion treatment regimen that would be efficacious in treatment of multi-drug resistance ovarian cancer would be beneficial. Additionally, methods and compositions that are easily administered are necessary. A simple and efficacious method of treatment would be through the oral route, particularly if the oral administration provides pharmacokinetic benefits similar the pharmacokinetics of the 96-hour infusion of paclitaxel.
In accordance with the present invention, compositions and methods are provided that are effective in treating ovarian cancer. These compositions are easily administered by long term infusion schedules of at least 72 hours, and can be given in dosages that are safe and provide for manageable side effects. The present invention provides methods and compositions for treating ovarian cancer in patients whose tumors progressed or failed to respond during prior taxane treatment of shorter duration and also treatment of patients who have previously undergone known chemotherapy treatment, such as treatment with platinum-based chemotherapy, and who are refractory to short-term taxane treatment. Surprisingly, it has been shown with the present invention that longer infusion periods, such as 96 hours, give substantially lower neuropathy and certain other side effects than shorter term infusions. Thus, the longer-infusion periods contemplated in the present invention obviate the need for premedications that other paclitaxel treatments require.
The present invention comprises methods and compositions for treating ovarian cancer with a long term exposure to paclitaxel. Such a schedule includes infusion times on the order of at least 72 hours, more preferably at least 96 hours. Such long term infusion schedules may enhance the activity of drugs, such as paclitaxel, which are transported by P-glycoprotein. Thus a preferred embodiment of the present invention is to administer paclitaxel as a 96 hour infusion treatment in patients with ovarian cancer, to effectively treat the ovarian cancer and to reduce the chances of developing mdr (multidrug resistance) paclitaxel resistance.
The present invention also includes ovarian cancer treatment compositions that contain paclitaxel. These ovarian cancer treatment compositions can be administered to humans with ovarian cancer at doses of 70 mg/m2 to 200 mg/m2, more preferably at doses of 100 mg/m2 to 175 mg/m2, most preferably 140 mg/m2, the dose level being dependent on the toxicity of paclitaxel to the patient.
Accordingly, it is an object of the present invention to provide methods and compositions to treat ovarian cancer.
It is yet another object of the present invention to provide methods of treatment of ovarian cancer comprising long term infusion schedules.
It is another object of the present invention to provide methods of treatment for patients with ovarian cancer that have had tumor progression after treatment with other chemotherapy regimens.
Another object of the present invention is to provide compositions comprising taxanes for the treatment of ovarian cancer.
It is yet another object of the present invention to provide a treatment for patients with ovarian cancer who were refractory to treatment with short term infusion treatment with taxanes.
A further object of the present invention is to provide methods and compositions for a treatment of ovarian carcinoma in patients who have undergone at least one prior chemotherapy regimen, including but not limited to platinum based therapies or taxane therapies, and who has had tumor progression.
It is another object of the present invention to provide methods and compositions of paclitaxel treatment that reduce or eliminate the development of mdr paclitaxel resistance.
It is another object of the present invention to provide methods and compositions of paclitaxel treatment that reduce or eliminate the need for premedication of the patients.
These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.